The thymus is a complex organ responsible for the maturation and education of peripheral T cells. Production of broadly reactive T cells and maintenance of a diverse peripheral T cell repertoire are critical to the success of the human immune system. Unfortunately, thymopoiesis is attenuated by normal aging. As an individual ages, the thymus involutes by unknown mechanisms and output of new T cells significantly falls. Loss of a broadly reactive naive peripheral T cell repertoire with age results in suppressed immune responses to infections and vaccines in adults. Moreover, when the adult peripheral T cell pool is damaged by viral infection (HIV), chemotherapy, or irradiation, there is a need to therapeutically reconstitute the periphery with new T cells. The functional status of the aged thymus dictates quantity and quality of T cell reconstitution and immunity. Thymic involution is an ordered process resulting in induction of thymocyte apoptosis. It has recently been demonstrated that IL-6 gene family cytokines are elevated in aged human and mouse thymus tissue, and that they actively suppress thymopoiesis in mice. These observations have lead to the hypothesis that age-induced thymic involution is an active process mediated by thymosuppressive cytokines. The overall goal of this proposal is to define critical factors and pathways involved in thymus tissue aging, and be poised to translate newly-defined therapeutic strategies to humans for improved immunity in a variety of clinical settings in adults. The proposed specific aims to accomplish this goal are to determine the mechanisms by which Leukemia Inhibitory Factor and other thymosuppressive cytokines induce thymus involution by defining cytokine and steroid production pathways that result in thymocyte depletion throughout aging, to determine if inhibition of Leukemia Inhibitory Factor and other thymosuppressive cytokines can prevent or reverse thymic atrophy of aging in mice, and to determine if improved thymic function in aged mice can enhance peripheral immune responses to infectious pathogens or vaccines.